Recent epidemiologic studies have shown that elevated levels of circulating insulin-like growth factor 1 (IGF-1) and decreased levels of circulating insulin-like growth factor binding protein 3 (IGFBP-3) are associated with increased risk of colorectal cancer. Many of the genes in the IGF axis are polymorphic, and studying this genetic variation as potential markers of susceptibility for colon cancer may have important implications for cancer prevention. As an adjunct to an existing population-based case-control study we propose to 1) evaluate the association between polymorphisms in IGF-1 and IGFBP-3 genes and colorectal cancer risk, and 2) to assess whether the associations between various lifestyle risk factors (such as hormone replacement therapy, physical activity, and obesity) and colorectal cancer are modified by the presence of these polymorphisms. Because the importance of polymorphisms in the IGF-1 and particularly the IGFBP-3 genes are not well understood, we additionally propose to determine whether these polymorphisms are associated with differential levels of circulating plasma IGF-1 and IGFBP-3 among cancer-free community controls. 400 men and women aged 20-74 years with a new diagnosis of colorectal cancer identified through the Puget Sound SEER registry and 400 community controls will be included in this proposed analysis. A structured telephone interview will assess HRT use, body size, physical activity, history, reproductive history, family history of cancer and demographic information. DNA from blood and buccal samples will be used to determine IGF polymorphism genotype. Plasma samples will e analyzed for circulating IGF-1 and IGFBP-3 levels. As an adjunct to an existing study, this is an efficient, valid cost-effective approach to the investigation of the association between polymorphisms and cancer risk.